Booting Up A Synthetic Genome (Updated for typos)

The press is all abuzz over the Venter Institute's paper last week demonstrating a functioning synthetic genome. Here is the Gibson et al paper in Science, and here are takes from the NYT and The Economist (lede, story). The Economist story has a figure with the cost and productivity data for gene and oligo synthesis, respectively. Here also are Jamais Cascio and Oliver Morton, who points to this collection of opinions in Nature.

The nuts and bolts (or bases and methylases?) of the story are this: Gibson et al ordered a whole mess of pieces of relatively short, synthetic DNA from Blue Heron and stitched that DNA together into full length genome for Bug B, which they then transplanted into a related microbial species, Bug A. The transplanted genome B was shown to be fully functional and to change the species from old to new, from A to B. Cool.

Yet, my general reaction to this is the same as it was the last time the Venter team claimed they were creating artificial life. (How many times can one make this claim?) The assembly and boot-up are really fantastic technical achievements. (If only we all had the reported $40 million to throw at a project like this.) But creating life, and the even the claim of creating a "synthetic cell"? Meh.

I am going to agree with my friends at The Economist (see main story) that the announcement is "not unexpected", and disagree strongly that "The announcement is momentous." DNA is DNA. We have known that for, oh, a long time now. Synthetic DNA that is biologically indistinguishable from "natural DNA" is, well, biologically indistinguishable from natural DNA. This result is at least thirty years old, when synthetic DNA was first used to cause an organism to do something new. There are plenty of other people saying this in print, so I won't belabor the point; see, for example, the comments in the NYT article.

One less-than-interesting outcome of this paper is that we are once again going to read all about the death of vitalism (see the Nature opinion pieces). Here are the first two paragraphs from Chapter 4 of my book:

"I must tell you that I can prepare urea without requiring a kidney of an animal, either man or dog." With these words, in 1828 Friedrich Wöhler claimed he had irreversibly changed the world. In a letter to his former teacher Joens Jacob Berzelius, Wöhler wrote that he had witnessed "the great tragedy of science, the slaying of a beautiful hypothesis by an ugly fact." The beautiful idea to which he referred was vitalism, the notion that organic matter, exempliﬁed in this case by urea, was animated and created by a vital force and that it could not be synthesized from inorganic components. The ugly fact was a dish of urea crystals on his laboratory bench, produced by heating inorganic salts. Thus, many textbooks announce, was born the ﬁeld of synthetic organic chemistry.

As is often the case, however, events were somewhat more complicated than the textbook story. Wöhler had used salts prepared from tannery wastes, which adherents to vitalism claimed contaminated his reaction with a vital component. Wöhler's achievement took many years to permeate the mind-set of the day, and nearly two decades passed before a student of his, Hermann Kolbe, ﬁrst used the word "synthesis" in a paper to describe a set of reactions that produced acetic acid from its inorganic elements.

Care to guess where the nucleotides came from that went into the Gibson et al synthetic genome? Probably purified and reprocessed from sugarcane. Less probably salmon sperm. In other words, the nucleotides came from living systems, and are thus tainted for those who care about such things. So much for another nail in the vital coffin.

Somewhat more intriguing will be the debate around whether it is the atoms in the genome that are interesting or instead the information conveyed by the arrangement of those atoms that we should care about. Clearly, if nothing else this paper demonstrates that the informational code determines species. This isn't really news to anyone who has thought about it (except, perhaps, to IP lawyers -- see my recent post on the breast cancer gene lawsuit) but it might get a broader range of people thinking more about life as information. What then, does "creating life" mean? Creating information? Creating sequence? And what sort of design tools do we need to truly control these creations? Are we just talking about much better computer simulations, or is there more physics to learn, or is it all just too complicated? Will we be forever chasing away ghosts of vitalism?

That's all I have for deep meaning at the moment. I've hardly just got off one set of airplanes (New York-DC-LA) and have to get on another for Brazil in the morning.

I would, however, point out that the recent paper describes what may be a species-specific processing hack. From the paper:

...Initial attempts to
extract the M. mycoides genome from yeast and transplant it into
M. capricolum failed. We discovered that the donor and recipient
mycoplasmas share a common restriction system. The donor genome was
methylated in the native M. mycoides cells and was therefore
protected against restriction during the transplantation from a native
donor cell. However, the bacterial genomes grown in yeast are
unmethylated and so are not protected from the single restriction system
of the recipient cell. We were able to overcome this restriction
barrier by methylating the donor DNA with purified methylases or crude M.
mycoides or M. capricolum extracts, or by simply disrupting
the recipient cell's restriction system.

This methylation trick will probably -- probably -- work just fine for other microbes, but I just want to point out that it isn't necessarily generalizable and that the JVCI team didn't demonstrate any such thing. The team got this one bug working, and who knows what surprises wait in store for the next team working on the next bug.

Since Gibson et al have in fact built an impressive bit of DNA, here is an updated "Longest Synthetic DNA Plot" (here is the previous version with refs.); alas, the one I published just a few months ago in Nature Biotech is already obsolete (hmph, they have evidently now stuck it behind a pay wall).

A couple of thoughts: As I noted in DNA Synthesis "Learning Curve": Thoughts on the Future of Building Genes and Organisms (July 2008), it isn't really clear to me that this game can go on for much longer. Once you hit a MegaBase (1,000,000 bases, or 1 MB) in length, you are basically at a medium-long microbial genome. Another order of magnitude or so gets you to eukaryotic chromosomes, and why would anyone bother building a contiguous chuck of DNA longer than that? Eventually you get into all the same problems that the artificial chromosome community has been dealing with for decades -- namely that chromatin structure is complex and nobody really knows how to build something like it from scratch. There is progress, yes, and as soon as we get a real mammalian artificial chromosome all sorts of interesting therapies should become possible (note to self: dig into the state of the art here -- it has been a few years since I looked into artificial chromosomes). But with the 1 MB milestone I suspect people will begin to look elsewhere and the typical technology development S-curve kicks in. Maybe the curve has already started to roll over, as I predicted (sketched in) with the Learning Curve.

Finally, I have to point out that the ~1000 genes in the synthetic genome are vastly more than anybody knows how to deal with in a design framework. I doubt very much that the JCVI team, or the team at Synthetic Genomics, will be using this or any other genome in any economically interesting bug any time soon. As I note in Chapter 8 of Biology is Technology, Jay Keasling's lab and the folks at Amyris are playing with only about 15 genes. And getting the isoprenoid pathway working (small by the Gibson et al standard but big by the everyone-else standard) took tens of person years and about as much investment (roughly ~$50 million in total by the Gates Foundation and investors) as Venter spent on synthetic DNA alone. And then is Synthetic Genomics going to start doing metabolic engineering in a microbe that they only just sequenced and about which relatively little is known (at least compared with E. coli, yeast, and other favorite lab animals)? Or they are going to redo this same genome synthesis project in a bug that is better understood and will serve as a platform or chassis? Either way, really? The company has hundreds of millions of dollars in the bank to spend on this sort of thing, but I simply don't understand what the present publication has to do with making any money.

So, in summary: very cool big chuck of synthetic DNA being used to run a cell. Not artificial life, and neither artificial cell nor synthetic cell. Probably not going to show up in a product, or be used to make a product, for many years. If ever. Confusing from the standpoint of project management, profit, and economic viability.

But I rather hope somebody proves me wrong about that and surprises me soon with something large, synthetic, and valuable. That way lies truly world changing biological technologies.

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There has been a lot of discussions about synthetic DNA, so while it is thought that the genetic catalog (spurred from the Human Genome Project) is largely complete, there are still plenty genetic paradigm we have to understand, and a new field introduced by Richard Francis also gets the topic heated again. His book is called Epigenetics: The Ultimate Mystery of Inheritance.